期刊
CIRCULATION RESEARCH
卷 115, 期 6, 页码 581-+出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.115.304718
关键词
angiogenesis; capillary permeability; stroke; vascular endothelial growth factor A
资金
- Portuguese Foundation for Science and Technology [SFRH/BPD/65373/2009]
- Max Planck Society
- University of Munster
- Fundação para a Ciência e a Tecnologia [SFRH/BPD/65373/2009] Funding Source: FCT
Rationale: Endothelial cell-specific molecule 1 (Esm1) is a secreted protein thought to play a role in angiogenesis and inflammation. However, there is currently no direct in vivo evidence supporting a function of Esm1 in either of these processes. Objective: To determine the role of Esm1 in vivo and the underlying molecular mechanisms. Methods and Results: We generated and analyzed Esm1 knockout (Esm1(KO)) mice to study its role in angiogenesis and inflammation. Esm1 expression is induced by the vascular endothelial growth factor A (VEGF-A) in endothelial tip cells of the mouse retina. Esm1(KO) mice showed delayed vascular outgrowth and reduced filopodia extension, which are both VEGF-A-dependent processes. Impairment of Esm1 function led to a decrease in phosphorylated Erk1/2 (extracellular-signal regulated kinases 1/2) in sprouting vessels. We also found that Esm1(KO) mice displayed a 40% decrease in leukocyte transmigration. Moreover, VEGF-induced vascular permeability was decreased by 30% in Esm1(KO) mice and specifically on stimulation with VEGF-A(165) but not VEGF-A(121). Accordingly, cerebral edema attributable to ischemic stroke-induced vascular permeability was reduced by 50% in the absence of Esm1. Mechanistically, we show that Esm1 binds directly to fibronectin and thereby displaces fibronectin-bound VEGF-A(165) leading to increased bioavailability of VEGF-A(165) and subsequently enhanced levels of VEGF-A signaling. Conclusions: Esm1 is simultaneously a target and modulator of VEGF signaling in endothelial cells, playing a role in angiogenesis, inflammation, and vascular permeability, which might be of potential interest for therapeutic applications.
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